PROJECT SUMMARY/ABSTRACT The overarching goal of this proposal is the development of the candidate into an independent, patient- oriented clinical investigator capable of leading rigorous research aimed at preserving cognitive health in youth with sickle cell disease (SCD). As a pediatric psychologist with experience in cognitive assessment and clinical research with children with SCD, the candidate is uniquely positioned to benefit from this NIH Mentored Career Development Award. SCD is an understudied, life-limiting disease affecting 100,000 individuals in the United States and over 300,000 newborns globally every year. Youth with SCD perform lower on tests of cognitive ability, even compared to healthy siblings. Overt stroke, while a substantial risk, does not affect the majority of patients with SCD yet there are clear indications of non-stroke, disease effects on the central nervous system. These cognitive deficits impact school achievement, employment, and disease management. Limitations of previous research have stifled translation of knowledge about cognitive deficits into clinical applications to preserve cognitive health in the absence of stroke. The proposed study will address unanswered questions by investigating the following specific aims: 1) determine the trajectory of cognitive functioning in youth with SCD without overt stroke; and 2) explore resting-state prefrontal-striatal functional connectivity in a subset of youth with SCD without overt stroke. In this study, 114 youth ages 8-17 with HbSS without stroke will complete computerized cognitive tests and blood draws every 6 months for 18 months, as well as transcranial Doppler ultrasonography at baseline and 12 months later. A subset (n=40) between ages 11-17 will complete resting-state functional magnetic resonance imaging at baseline. Results will advance the field toward prevention of all SCD- related cognitive deficits in the absence of stroke by enhancing predictive models that identify patients at risk for future cognitive declines and informing strategic application of cognitive and disease-modifying treatments. The candidate has organized an exemplary mentorship team with notable records of NIH funding and mentorship who are committed to advancing the candidate's career. Mentors have expertise in longitudinal cognitive assessment (Dr. Kristina Hardy), SCD pathophysiology (Dr. Naomi Luban), cognitive functioning in SCD (Dr. Jeffrey Schatz), functional neuroimaging (Dr. Chandan Vaidya), SCD severity measurement models (Dr. Julie Panepinto), and research design and biostatistics (Dr. Jichuan Wang). The candidate will benefit from an ideal academic environment and extensive resources in Children's National Health System. A structured training plan will ensure timely progress toward career development goals involving acquisition of knowledge about: 1) SCD pathophysiology and disease severity measurement; 2) fMRI design and interpretation; and 3) advanced clinical research methods. Taken together, the proposed plan will provide the candidate with the preliminary data and mentorship needed for him to be a competitive candidate for independent research funding, while also positioning him as a leader in the field of cognitive outcomes in SCD.